Cytotoxic CD8+ T Cells Downregulate GPX4 to Promote Ferroptosis in Melanoma That Drives Antitumor Immunity

Identifying factors that mediate successful anticancer immune responses is necessary to improve outcomes for patients with advanced cancers. In this study, we performed single-cell RNA sequencing on mouse melanomas experiencing successful and unsuccessful immune responses and discovered a prominent ferroptosis signature in tumors undergoing immune-mediated regression. Pairing ferroptosis inducers and inhibitors with immunotherapies ex vivo and in vivo highlighted a central role for ferroptosis in stimulating the antimelanoma immune response. In coculture models, CD8+ T cells drove melanoma cell ferroptosis by altering the expression of glutathione peroxidase 4 (GPX4), a crucial antioxidant enzyme known for its role in preventing lipid peroxidation. Direct contact between tumor cells and CD8+ T cells was needed to sustain GPX4 downregulation over time, resulting in ferroptotic cell death. Finally, single-cell RNA sequencing data from human melanoma tumors responding to immunotherapy revealed a ferroptosis signature that mirrors the mouse model. Together, these results offer crucial insights into the role of ferroptosis in antitumor immunity and highlight the potential of modulating ferroptosis to enhance immunotherapy responses. SIGNIFICANCE: CD8+ T cells directly interact with melanoma cells to downregulate the essential antioxidant enzyme GPX4 and stimulate ferroptosis, which is a crucial driver of immune cell-mediated melanoma clearance.